PB2481: OUTCOMES OF INDIVIDUALS WITH CLONAL HEMATOPOIESIS EVALUATED AT A CANCER CENTER
Authors: Kelly Chien, Faustine Ong, Kunhwa Kim, Ziyi LI, Rashmi Kanagal-Shamanna, Courtney Dinardo, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Koji Sasaki, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: HemaSphere (2023)

Topic: 23. Hematopoiesis, stem cells and microenvironment Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Aims: Here, we assess the clinical characteristics and outcomes, including survival and leukemic transformation, of patients with CH evaluated at a cancer center. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had cardiovascular comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). Twenty CCUS patients (26%) received treatment for cytopenias, such as growth factors, corticosteroids, other non-steroidal immunosuppressants, and iron supplementation. The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%), with the time to transformation not reached in all cohorts. At the time of transformation, 2 patients (17%) developed new cytogenetic abnormalities, and 5 patients (42%) acquired new mutations with ASXL1 the most frequently attained (40%) (Figure). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p=0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin < 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p=0.0005) and hemoglobin < 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p=0.0005). When applying the recently-presented Clonal Hematopoiesis Risk Score these patients, the 3-year cumulative incidence of transformation 0% in low-risk, 15% in intermediate-risk, and 28% in the high-risk groups (p=0.16). Summary/Conclusion: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.Keywords: Clonal cytopenia of undeterminated significance, Clonal hematopoiesis of indeterminate potential, Leukemic transformation, Myeloid malignancies